Cognitive and/or degenerative brain disorders are characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. In an example of such disorders, Alzheimer's Disease (AD) is a common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. In particular, AD is associated with degeneration of cholinergic neurons in the basal forebrain that play a fundamental role in cognitive functions, including memory (Becker et al., Drug Development Research, 1988, 12, 163-195). Cognitive and degenerative brain disorders have been observed in varied races and ethnic groups worldwide and present a major public health problem. These diseases are currently estimated to affect about two to three million individuals in the United States alone. These diseases are incurable with presently-used medications and will increase worldwide as the human life span increases.
Serotonin receptors have been divided into a number of families and subfamilies (5-HT1 through 5-HT7) and approximately 14 populations have been cloned. One of the newest populations identified is the 5-HT6 subtype. It has been observed that various tricyclic psychotropic agents (neuroleptics, antidepressants, and atypical neuroleptic agents) bind the 5-HT6 receptor with nanomolar affinities (Roth et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403-1410). A rat 5-HT6 receptor was first cloned in 1993 and, more recently, the same group described the cloning of a human 5-HT6 receptor. The 5-HT6 receptors are members of the G-protein superfamily, are positively coupled to an adenylate cyclase second messenger system and are found primarily in the central nervous system. Serotonin bound to the 5-HT6 receptor subgroup activates the adenylate cyclase enzyme, with concomitant increased levels of intracellular cAMP. Although the exact physiological function and clinical significance of the 5-HT6 receptor subgroup is not known, as noted above, many anti-psychotic agents bind these receptors with high affinity. Also, rats that do not express 5-HT6 receptors behave in a manner that seems to involve an increase in cholinergic function.
The 5-HT2A receptor subtype is widely yet discretely expressed in the human brain, including many cortical, limbic, and forebrain regions. This receptor subtype is highly expressed on blood vessel smooth muscle (e.g. aorta and femoral artery) where 5-HT is known to mediate contraction. It is also expressed on mature platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis. Recent studies have shown that antagonism of the 5-HT2A receptor is an alternate molecular mechanism for drugs with antipsychotic efficacy, possibly through antagonism of heightened or exaggerated signal transduction through serotonergic systems. 5-HT2A antagonists are therefore candidates for treating psychosis without extrapyramidal side effects. However, the involvement of the 5-HT2A receptor in cognitive functions is not fully understood and is considered controversial, with studies showing the stimulation of the 5-HT2A receptor to be either cognition-enhancing or impairing (Williams et al., J. Neurosci., 2002, 22, 2843-2854; Harvey, Learn. Mem., 2003, 10, 355-362, Umbricht et al., Neuropsycho-pharmacology, 2003, 28, 170-181).
Atypical antipsychotic drugs such as clozapine or olanzapine, which are non-selective antagonists of the 5-HT6 and 5-HT2A receptors, have been implicated in improving cognitive function but they may also show adverse effects such as delirium and confusion (Mori et al., Prog. Neuropsycho-pharmacol. Biol. Psychiatry, 2004, 28, 659-665; Kennedy et al., Int. J. Geriatr. Psychology, 2001, 16, S33-S61). However these drugs have been tested only in psychotic patients and their efficacy in improving cognition in non-psychotic patients is not understood.